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WO2014181840A1 - Timbre adhésif - Google Patents

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Publication number
WO2014181840A1
WO2014181840A1 PCT/JP2014/062392 JP2014062392W WO2014181840A1 WO 2014181840 A1 WO2014181840 A1 WO 2014181840A1 JP 2014062392 W JP2014062392 W JP 2014062392W WO 2014181840 A1 WO2014181840 A1 WO 2014181840A1
Authority
WO
WIPO (PCT)
Prior art keywords
rotigotine
acid
adhesive layer
patch
weight
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2014/062392
Other languages
English (en)
Japanese (ja)
Inventor
弘幸 荻野
後藤　正興
充代 濱田
満児 赤澤
定生 行本
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
KM Transderm Ltd
Original Assignee
KM Transderm Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by KM Transderm Ltd filed Critical KM Transderm Ltd
Publication of WO2014181840A1 publication Critical patent/WO2014181840A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a patch containing rotigotine. More specifically, the present invention relates to a patch having high skin permeability of rotigotine, good transdermal absorbability and low skin irritation.
  • Parkinson's disease and restless legs syndrome in which discomfort such as pain and itching appear in the soles and calves of the foot, and are driven to the situation where the leg must be moved to suppress this, are thought to occur.
  • the therapeutic effect of rotigotine, ie (6S) -6- ⁇ propyl [2- (2-thienyl) ethyl] amino ⁇ -5,6,7,8-tetrahydro-1-naphthalenol, on Parkinson's disease is mainly By stimulating the D2-like receptor in the postsynaptic membrane of the body dopamine nerve, it is due to activation of transmission of the dopamine nervous system, and a therapeutic effect can be obtained by the same mechanism for restless legs syndrome It is believed that.
  • Rotigotine is a non-ergot dopamine agonist, so there are few gastrointestinal symptoms such as nausea often seen with ergot dopamine agonists, stable treatment for Parkinson's disease, and suppression of motor complications Has characteristics. Furthermore, it has an effect on restless legs syndrome and has already been widely used as the first-line drug in Europe and America.
  • New Pro Patch a transdermal preparation (patch) of rotigotine. Since the rotigotine is absorbed slowly from the skin and can maintain a sufficient blood concentration for a long time, the patch can provide a stable effect for 24 hours when applied once a day. As a result, in Parkinson's disease, there is no need to worry about the early effects of drug outage, and restless legs syndrome can cover daytime symptoms in addition to nighttime.
  • Non-patent Document 1 Non-patent Document 1
  • Parkinson's disease often develops in the 50s and 60s, and the incidence and prevalence increase with age.
  • the moisturizing function is lowered and dried due to a decrease in the production of sebum, and the barrier function of the skin tends to be lowered.
  • a patch having strong skin irritation is applied to such an elderly patient, there is a very high possibility that some harmful phenomenon will occur on the skin.
  • the present inventors tried to develop a patch containing rotigotine as a drug using the adhesive layer components described in Patent Documents 3 to 6, for example.
  • a patch having a conventional pressure-sensitive adhesive layer containing a rubber-based pressure-sensitive adhesive or the like sufficient release of rotigotine cannot be ensured.
  • it is usually necessary to add a tackifier in order to impart sufficient skin tackiness but it has also been found that skin irritation occurs due to the tackifier.
  • an object of the present invention is to provide a patch having sufficient skin adhesiveness, low skin irritation, good skin permeability of rotigotine, and sufficient transdermal absorbability. It is to provide.
  • the present inventors have used a thermoplastic elastomer and a non-volatile hydrocarbon oil having a specific weight ratio with respect to the elastomer as components for forming the pressure-sensitive adhesive layer. And by reducing the content of the tackifier, it was possible to reduce skin irritation while ensuring sufficient skin adhesiveness. Furthermore, since the skin permeability of rotigotine was good and sufficient transdermal absorbability was exhibited, the present invention was completed.
  • the present invention relates to the following [1] to [12].
  • [1] A patch in which a pressure-sensitive adhesive layer containing rotigotine or a salt thereof is formed on a support, The pressure-sensitive adhesive layer Rotigotine or a salt thereof, A patch comprising a thermoplastic elastomer and a non-volatile hydrocarbon oil of more than 50 parts by weight and less than 800 parts by weight with respect to 100 parts by weight of the elastomer.
  • the thermoplastic elastomer is a styrene block copolymer.
  • the styrene block copolymer is a styrene-isoprene-styrene block copolymer.
  • the pressure-sensitive adhesive layer may further contain a tackifier, and the content of the tackifier in the pressure-sensitive adhesive layer is 10% by weight or less, and any one of the above [1] to [5] The patch according to the description.
  • the patch of the present invention has good skin permeability of rotigotine and shows excellent transdermal absorbability. Moreover, it has sufficient skin adhesiveness when applied to the skin and has low skin irritation.
  • the patch of the present invention contains rotigotine in the adhesive layer as an active ingredient to be percutaneously absorbed.
  • rotigotine not only a free form of rotigotine (that is, a free (base) form of rotigotine) but also a salt of rotigotine can be used.
  • the adhesive patch of the present invention has a pressure-sensitive adhesive layer formed on a support, and the pressure-sensitive adhesive layer is more than 50 parts by weight and less than 800 parts by weight with respect to 100 parts by weight of the thermoplastic elastomer.
  • the pressure-sensitive adhesive layer may contain a tackifier, and when it contains a tackifier, the content in the pressure-sensitive adhesive layer is 10% by weight or less.
  • rotigotine salts include rotigotine and monocarboxylic acids such as acetic acid, propionic acid, and butyric acid; oxalic acid, malonic acid, fumaric acid, succinic acid, maleic acid, etc.
  • Dicarboxylic acids such as hydroxyacetic acid, lactic acid, malic acid, citric acid and tartaric acid; carbonic acid; alkanesulfonic acids such as methanesulfonic acid and ethanesulfonic acid; acid addition salts with organic acids such as amino acids such as glutamic acid, Examples include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid. Among these, rotigotine hydrochloride is preferable from the viewpoint of availability and dispersibility in the pressure-sensitive adhesive layer.
  • rotigotine can be used by selecting one or more from the group consisting of free (base) rotigotine and the above-mentioned rotigotine salt. From the viewpoint of dispersibility in the pressure-sensitive adhesive layer and transdermal absorbability, it is preferable to use free (base) type rotigotine.
  • base free (base) type rotigotine.
  • rotigotine when “rotigotine” is not described as “rotigotine or a salt thereof”, it simply means “free (base) type rotigotine and / or a salt of rotigotine”.
  • the content of rotigotine in the patch is not particularly limited, but in consideration of dispersibility and transdermal absorbability in the pressure-sensitive adhesive layer, it is preferably 1% by weight to 30% by weight, more preferably 2% by weight in the pressure-sensitive adhesive layer. -25% by weight, most preferably 3% -20% by weight.
  • thermoplastic elastomer used in the present invention is an elastomer that exhibits fluidity when softened and exhibits fluidity, and returns to a rubber-like elastic body when cooled.
  • styrene-based thermoplastic elastomers, particularly styrene-based block copolymers are preferably used.
  • styrene block copolymer examples include a styrene-butadiene block copolymer, a styrene-butadiene-styrene block copolymer, a styrene-isoprene block copolymer, a styrene-isoprene-styrene block copolymer, Styrene-ethylene / butylene block copolymer, styrene-ethylene / butylene-styrene block copolymer, styrene-ethylene / propylene block copolymer, styrene-ethylene / propylene-styrene block copolymer, styrene-isobutylene block copolymer And a styrene-isobutylene-styrene block copolymer.
  • ethylene / butylene represents a copolymer block of ethylene and butylene
  • ethylene / propylene represents a copolymer block of ethylene and propylene
  • styrene block copolymers styrene-isoprene-styrene block copolymers and / or from the viewpoints of sufficient skin adhesiveness and low skin irritation, as well as the availability and handling of patch products.
  • a styrene-isoprene block copolymer is preferable, and a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer are particularly preferable.
  • the mixing ratio of the styrene-isoprene block copolymer is preferably 10/90 to 82/18, more preferably 20/80 to 75/25, More preferred is 30/70 to 70/30.
  • the styrene-isoprene-styrene block copolymer preferably has a styrene content of 5% by weight to 60% by weight, more preferably 10% by weight to 50% by weight. Further, those having a weight average molecular weight measured by gel filtration chromatography of 20,000 to 500,000 are preferred, and those having a weight average molecular weight of 30,000 to 300,000 are more preferred.
  • the styrene-isoprene block copolymer preferably has a styrene content of 5 to 50% by weight, more preferably 10 to 40% by weight. Further, those having a weight average molecular weight measured by gel filtration chromatography of 10,000 to 500,000 are preferred, and those having a weight average molecular weight of 20,000 to 300,000 are more preferred.
  • styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer copolymers produced by a method known per se can be used.
  • styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer commercially available products that satisfy the above characteristics can be used.
  • a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer is also commercially available.
  • a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer satisfying the above characteristics Can be suitably used as a commercial product of a mixture in which is mixed at the above mixing ratio.
  • KRATON D manufactured by KRATON POLYMERS
  • JSR SIS manufactured by JSR
  • JSR Quality of Service
  • Quintac manufactured by Nippon Zeon
  • thermoplastic elastomer content in the adhesive layer of the patch of the present invention is preferably 8% by weight to 66% by weight, more preferably 10% by weight to 65% by weight, and particularly preferably 12% by weight or more. 64% by weight.
  • the pressure-sensitive adhesive layer contains a nonvolatile hydrocarbon oil together with the thermoplastic elastomer.
  • the nonvolatile hydrocarbon oil is preferably a chain saturated hydrocarbon having about 20 to 40 carbon atoms or a chain unsaturated hydrocarbon having about 20 to 40 carbon atoms, and examples thereof include liquid paraffin, squalene, squalane and pristane. .
  • liquid paraffin is more preferable from the viewpoint of easy availability.
  • the liquid paraffin is a colorless and odorless liquid mixture of alkanes having 20 or more carbon atoms.
  • a liquid paraffin that conforms to the standards prescribed in the Japanese Pharmacopoeia, the US Pharmacopoeia, and the like can be preferably used.
  • liquid paraffin having a high viscosity is preferably used from the viewpoint of tackiness.
  • the non-volatile hydrocarbon oil preferably has a kinematic viscosity at 40 ° C. of 60 mm 2 / s or more, more preferably 70 mm 2 / s or more, and still more preferably 80 mm 2 / s or more.
  • the upper limit of kinematic viscosity is not specifically limited, For example, 500 mm ⁇ 2 > / s or less is preferable and 250 mm ⁇ 2 > / s or less is more preferable from viewpoints of the ease of handling, availability, etc.
  • “Kinematic viscosity” as used herein refers to “Method 2 rotational viscometer (2.12 single cylinder rotational viscometer (Brooks)” in “2.53 Viscosity measurement method” of the general test method of “16th revised Japanese Pharmacopoeia”. This is a value obtained by converting the viscosity (mPa ⁇ s) measured in accordance with “field type viscometer” (page 59) into kinematic viscosity.
  • the patch of the present invention contains the above-described nonvolatile hydrocarbon oil in a weight ratio of more than 50 parts by weight and not more than 800 parts by weight with respect to 100 parts by weight of the thermoplastic elastomer.
  • the content of the non-volatile hydrocarbon oil with respect to 100 parts by weight of the thermoplastic elastomer exceeds 800 parts by weight, it becomes difficult to maintain the shape of the pressure-sensitive adhesive layer.
  • the content of the non-volatile hydrocarbon oil is 50 parts by weight or less, there is a tendency that sufficient adhesiveness to the skin cannot be obtained due to the adhesive becoming too hard, particularly following the movement of the skin at the time of application. It may worsen and fall off during application.
  • the content of the nonvolatile hydrocarbon oil in the pressure-sensitive adhesive layer is preferably 51 parts by weight to 800 parts by weight, more preferably 60 parts by weight to 600 parts by weight with respect to 100 parts by weight of the thermoplastic elastomer.
  • the most preferred amount is 70 to 500 parts by weight.
  • the content of the non-volatile hydrocarbon oil in the pressure-sensitive adhesive layer is preferably 23.5% by weight to 88% by weight, more preferably 25% by weight to 85% by weight, and still more preferably 26%, based on the whole pressure-sensitive adhesive layer. .5 wt% to 83 wt%, most preferably 40 wt% to 70 wt%.
  • the patch of the present invention may contain an antioxidant from the viewpoint of preventing oxidative deterioration of rotigotine and thermoplastic elastomer.
  • the antioxidant include tocopherol ester derivatives such as dibutylhydroxytoluene, ascorbic acid stearate, tocopherol, and tocopherol acetate, butylhydroxyanisole, 2-mercaptobenzimidazole, anthocyanin, catechin and the like. These may be used alone or in combination of two or more.
  • the content of the antioxidant is preferably 0.01% by weight to 5% by weight and more preferably 0.05% by weight to 1% by weight with respect to the total amount of the pressure-sensitive adhesive layer.
  • the pressure-sensitive adhesive layer further comprises an alcohol solvent, an amide solvent, an ester solvent, a liquid organic acid, a carboxylic acid.
  • You may contain 1 type, or 2 or more types selected from the group which consists of salt, lactone, and surfactant.
  • liquid of “liquid organic acid” means liquid at normal temperature. “Normal temperature” in the present specification is in the range of 15 to 25 ° C. according to the 16th revised Japanese Pharmacopoeia.
  • alcohol solvents include higher saturated aliphatic alcohols that are liquid at room temperature of about 12 to 20 carbon atoms such as lauryl alcohol, isostearyl alcohol, and 2-octyldodecanol; and about 12 to 20 carbon atoms such as oleyl alcohol.
  • higher unsaturated aliphatic alcohols that are liquid at normal temperature
  • polyhydric alcohols that are liquid at normal temperature such as ethylene glycol, propylene glycol, glycerin, 1,3-butanediol, and polyethylene glycol having a molecular weight of about 100 to 600.
  • the alcohol solvent is preferably a polyhydric alcohol that is liquid at room temperature from the viewpoint of improving the solubility of rotigotine, such as ethylene glycol, propylene glycol, 1,3-butanediol, polyethylene glycol having a molecular weight of about 100 to 600, and the like.
  • a diol that is liquid at room temperature is more preferable.
  • amide solvents include pyrrolidone such as N-methyl-2-pyrrolidone and 2-pyrrolidone; imidazolidinone such as 1,3-dimethyl-2-imidazolidinone; N-substituted toluidine such as crotamiton; formamide, N And alkaneamides such as methylformamide, N, N-dimethylformamide, N-methylacetamide, N, N-dimethylacetamide, N-methylpropanamide, and the like.
  • N-methyl-2-pyrrolidone, crotamiton, N, N-dimethylformamide, and N, N-dimethylacetamide are preferable from the viewpoint of improving the solubility, dispersibility, and transdermal absorbability of rotigotine.
  • N-methyl-2-pyrrolidone and crotamiton are more preferable.
  • ester solvent examples include esters of long-chain fatty acids and monovalent aliphatic alcohols, medium-chain fatty acid triglycerides, esters of polyvalent carboxylic acids and monovalent aliphatic alcohols, and carbonates.
  • the ester of a long chain fatty acid and a monovalent aliphatic alcohol is preferably an ester liquid at room temperature of a long chain saturated fatty acid having 12 to 20 carbon atoms and a monovalent aliphatic alcohol having 1 to 20 carbon atoms.
  • Room temperature liquid such as ethyl myristate, isopropyl myristate, octyldodecyl myristate liquid at room temperature such as ethyl myristate, ethyl palmitate, isopropyl palmitate, isostearyl palmitate, etc.
  • Room temperature such as palmitic acid ester, isopropyl stearate, etc. And liquid stearates.
  • An ester of a long-chain unsaturated fatty acid having 12 to 20 carbon atoms and a monovalent aliphatic alcohol having 1 to 20 carbon atoms can also be preferably used.
  • examples thereof include oleic acid esters that are liquid at normal temperature, ethyl linoleate, isopropyl linoleate, and other linoleic acid esters that are liquid at normal temperatures.
  • Medium-chain fatty acid triglycerides are triglycerides that are liquid at room temperature and are composed of fatty acids having about 6 to 12 carbon atoms such as caproic acid, caprylic acid, capric acid, lauric acid, and glycerin.
  • liquid fats and oils can also be used at normal temperature containing many of these. Examples of such fats and oils include peanut oil, olive oil, castor oil and the like.
  • medium chain fatty acid triglyceride liquid at room temperature or a medium chain fatty acid triglyceride-containing oil that is liquid at room temperature
  • products marketed for pharmaceuticals can be used as a medium chain fatty acid triglyceride liquid at room temperature.
  • esters of polyvalent carboxylic acids and monovalent aliphatic alcohols include, for example, liquid adipic acid diesters such as diethyl adipate and diisopropyl adipate, diethyl sebacate, diisopropyl sebacate, dioctyldodecyl sebacate and the like
  • a diester that is liquid at room temperature with a dicarboxylic acid having 2 to 12 carbon atoms and a monovalent aliphatic alcohol having 1 to 20 carbon atoms, such as sebacic acid diester that is liquid at normal temperature, can be given.
  • carbonic acid ester examples include cyclic carbonic acid esters of carbonic acid and diols having 2 to 10 carbon atoms, such as ethylene carbonate, propylene carbonate, vinylene carbonate, and propylene carbonate is preferred.
  • myristic acid ester myristic acid ester, medium chain fatty acid triglyceride mixture, sebacic acid diester and carbonate are preferable, and isopropyl myristate, caprylic acid and capric acid triglyceride mixture, diethyl sebacate and propylene carbonate are more preferable. .
  • the above alcohol solvents, amide solvents and ester solvents can be used by selecting one or more of them as necessary.
  • the content of these solvents is preferably 0.1% by weight to 20% by weight and more preferably 0.5% by weight to 15% by weight with respect to the total amount of the pressure-sensitive adhesive layer.
  • liquid organic acids examples include aliphatic saturation such as acetic acid, propionic acid, butyric acid, valeric acid, isovaleric acid, caproic acid, enanthic acid (heptanoic acid), caprylic acid, and pelargonic acid (nonanoic acid).
  • examples thereof include hydroxycarboxylic acids; liquid carboxylic acids substituted with alkoxy groups such as methoxyacetic acid; and sulfonic acids such as methanesulfonic acid. These may be used alone or in combination of two or more.
  • liquid organic acids have a function of assisting dissolution of rotigotine.
  • low-solubility rotigotine can be contained in the adhesive layer at a high concentration, and the dispersibility of rotigotine is also improved. And has the effect of improving transdermal absorbability.
  • aliphatic unsaturated monocarboxylic acids and hydroxycarboxylic acids are preferable, Japanese pharmacopoeia lactic acid and oleic acid are more preferable, and oleic acid is particularly preferably used.
  • the content of the liquid organic acid is preferably 0.1% by weight to 20% by weight, and more preferably 0.5% by weight to 15% by weight with respect to the total amount of the pressure-sensitive adhesive layer. Further, the content of the liquid organic acid with respect to rotigotine in the pressure-sensitive adhesive layer is preferably 0.75 to 1.05 molar equivalent, more preferably 0.80 to 1.03 molar equivalent, and particularly preferably. Is 1.00 molar equivalent. When the content is less than the above 0.75 molar equivalent, the improvement in solubility of rotigotine may be insufficient, and when the content is higher than 1.05 molar equivalent, the liquid organic acid may be oozed out. There is.
  • examples of the carboxylate include salts of aliphatic monocarboxylic acid, alicyclic monocarboxylic acid, aliphatic dicarboxylic acid and the like.
  • Examples of the aliphatic monocarboxylic acid include short chain fatty acids having 2 to 7 carbon atoms such as acetic acid, butyric acid and hexanoic acid, for example, medium chain fatty acids having 8 to 11 carbon atoms such as octanoic acid and decanoic acid, such as myristic acid, Substituted with a long chain fatty acid having 12 or more carbon atoms such as stearic acid, isostearic acid and oleic acid, for example, a hydroxy monocarboxylic acid such as glycolic acid, lactic acid, 3-hydroxybutyric acid and mandelic acid, for example, an alkoxy group such as methoxyacetic acid Examples thereof include monocarboxylic acids such as ketomonocarboxylic acids such as levulinic acid.
  • Examples of the alicyclic monocarboxylic acid include alicyclic monocarboxylic acids having 6 to 8 carbon atoms such as cyclohexane carboxylic acid.
  • Examples of the aliphatic dicarboxylic acid include sebacic acid, adipic acid, malic acid, maleic acid, fumaric acid and the like.
  • Preferred carboxylic acids include long chain fatty acids having 12 or more carbon atoms, hydroxy monocarboxylic acids and the like, more preferably, myristic acid, stearic acid, isostearic acid, oleic acid, lactic acid and the like, Particularly preferred are oleic acid and lactic acid.
  • Examples of the carboxylate include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt; amine salts, etc., but are easily available, stable and transdermally absorbable. From the viewpoint of the improvement effect, alkali metal salts are preferable, and sodium salts are particularly preferably used.
  • sodium oleate and sodium lactate are particularly preferable as the carboxylate.
  • examples of the lactone include 5-membered ring lactones such as ascorbic acid and isoascorbic acid.
  • the content of the pressure-sensitive adhesive layer in the case where the pressure-sensitive adhesive layer contains a carboxylate or a lactone is not particularly limited, but is preferably 0.1 mol or more and 5 mol or less, more preferably, 1 mol of rotigotine. It is 0.2 mol or more and 3 mol or less.
  • the addition amount relative to 1 mol of rotigotine is less than 0.1 mol, a sufficient transdermal absorbability improvement effect may not be obtained.
  • the addition amount relative to 1 mol of rotigotine is more than 5 mol, adhesive properties The physical properties of the preparation may deteriorate.
  • surfactants include polyoxyethylene fatty acid esters such as polyoxyethylene monolaurate, polyoxyethylene sorbite fatty acid esters such as polyoxyethylene sorbite tetraoleate, polyoxyethylene sorbitan monooleate, polyoxyethylene Polyoxyethylene sorbitan fatty acid esters such as ethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, sorbitan fatty acid esters such as sorbitan monolaurate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, glycerin monooleate Glycerin fatty acid ester such as polyoxyethylene castor oil derivative, polyoxyethylene hydrogenated castor oil, polyoxyethylene lauryl ether , Polyoxyethylene higher aliphatic alcohol ethers such as polyoxyethylene oleyl ether, polyoxyethylene alkylphenyl ethers such as polyoxyethylene nonylphenyl ether, polyoxyethylene
  • nonionic surfactants that are liquid at room temperature are preferred
  • sorbitan fatty acid esters that are liquid at room temperature are more preferred
  • sorbitan monolaurate is particularly preferred, in order to enhance transdermal absorbability.
  • the content in the pressure-sensitive adhesive layer is preferably 0.01% by weight to 10% by weight, more preferably 0.1% by weight to 5% by weight.
  • the adhesive layer containing thermoplastic elastomer and nonvolatile hydrocarbon oil at the content and content ratio as described above can exhibit good skin adhesiveness.
  • the pressure-sensitive adhesive layer may contain a tackifier.
  • the tackifier is a resin generally used for imparting skin adhesiveness in the field of patches, and includes, for example, rosin resin, polyterpene resin, coumarone / indene resin, petroleum resin, terpene / phenol. Examples thereof include resins and alicyclic saturated hydrocarbon resins, and one or more of them can be selected and used.
  • the content of the tackifier when the pressure-sensitive adhesive layer contains the tackifier is 10% by weight or less.
  • the content is preferably 5% by weight or less, more preferably 2% by weight or less, still more preferably 1% by weight or less, and most preferably no tackifier.
  • the content of the tackifier is adjusted according to the type, content, and content ratio of the thermoplastic elastomer and the non-volatile hydrocarbon oil in relation to the skin adhesiveness of the patch.
  • an excipient for example, a dispersant, a stabilizer, a thickener, a softener, a flavoring agent, as long as the characteristics of the present invention are not impaired.
  • Additives generally used in pharmaceutics such as coloring agents may be contained.
  • excipients examples include silicon compounds such as silicic anhydride, light anhydrous silicic acid, and hydrous silicic acid; cellulose derivatives such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose; synthetic water-soluble polymers such as polyvinyl alcohol
  • An aluminum compound such as dry aluminum hydroxide gel or hydrous aluminum silicate; a pigment such as kaolin or titanium oxide;
  • excipients can be selected and used.
  • dispersant examples include gum arabic, propylene glycol alginate, sodium dioctyl sulfosuccinate, lecithin and the like.
  • One or more dispersants can be selected and used.
  • Stabilizers include zinc stearate, gelatin, dextran, povidone and the like. One or more stabilizers can be selected and used.
  • thickening agent examples include carboxyvinyl polymer, xanthan gum, tragacanth, locust bean gum and the like.
  • One or more thickeners can be selected and used.
  • softening agent examples include almond oil, rapeseed oil, cottonseed oil / soybean oil mixture, process oil, beef tallow, etc .; waxes such as refined lanolin; solid esters at room temperature such as cetyl lactate; polyisoprene rubber , Rubbers such as polybutene and raw rubber; polymers such as crystalline cellulose; and allantoin.
  • waxes such as refined lanolin
  • solid esters at room temperature such as cetyl lactate
  • polyisoprene rubber Rubbers such as polybutene and raw rubber
  • polymers such as crystalline cellulose
  • allantoin One or more softening agents can be selected and used.
  • flavoring agents examples include d-camphor, dl-camphor, d-borneol, dl-borneol, cinnamaldehyde, mint oil, dl-menthol, and l-menthol.
  • One or more flavoring agents can be selected and used.
  • Coloring agents include bengara, yellow iron oxide, yellow ferric oxide, carbon black and the like. One or more colorants can be selected and used.
  • an antioxidant it is preferable not to use an antioxidant, but it may be used as long as it does not affect skin irritation.
  • the patch of the present invention is prepared by spreading an adhesive layer having the above structure on a support.
  • the “support” is not particularly limited, and those widely used for patches can be used.
  • stretchable or non-stretchable woven fabrics such as polyethylene and polypropylene, non-woven fabrics, polyesters such as polyethylene, polypropylene, and polyethylene terephthalate, ethylene vinyl acetate copolymers, films such as vinyl chloride, and foaming properties such as urethane and polyurethane
  • a support is mentioned. These may be used alone or may be a laminate of a plurality of types.
  • an antistatic agent may be contained in the woven fabric, non-woven fabric, film, etc. constituting the support.
  • a nonwoven fabric or woven fabric, or a laminate of these and a film can be used as the support.
  • the thickness of the support is usually 10 ⁇ m to 100 ⁇ m, preferably 15 ⁇ m to 50 ⁇ m for a film, and usually 50 ⁇ m to 2,000 ⁇ m, preferably 100 ⁇ m to 100 ⁇ m for porous sheets such as woven fabrics, non-woven fabrics and foamed supports. 1,000 ⁇ m.
  • the patch of the present invention can also be provided with a release liner that is common in the field of patches.
  • a release liner glassine paper, polyester such as polyethylene, polypropylene, polyethylene terephthalate, resin film such as polystyrene, aluminum film, foamed polyethylene film or foamed polypropylene film, or a laminate of two or more of the above may be used. Further, those processed with silicone, processed with fluororesin, processed with embossing, hydrophilic processing, hydrophobic processing, etc. can be used.
  • the thickness of the release liner is usually 10 ⁇ m to 200 ⁇ m, preferably 15 ⁇ m to 150 ⁇ m.
  • the patch of the present invention comprises, for example, a thermoplastic elastomer and rotigotine or a salt thereof dissolved in a non-volatile hydrocarbon oil and dissolved or dispersed in a solvent such as toluene. And the obtained coating liquid is applied to a support and then dried.
  • the release liner can be pressure-bonded to the pressure-sensitive adhesive layer and laminated.
  • the coating liquid may be applied onto a release liner, dried to form a pressure-sensitive adhesive layer on the surface of the release liner, and then the support may be pressure bonded onto the pressure-sensitive adhesive layer and bonded together.
  • the coating solution for forming the pressure-sensitive adhesive layer is performed by using a conventional coater such as a roll coater, die coater, gravure roll coater, reverse roll coater, kiss roll coater, dip roll coater, bar coater, knife coater, spray coater, etc. Can be used.
  • the coating liquid is preferably dried under heating, for example, at a temperature of about 40 ° C. to 150 ° C.
  • the pressure-sensitive adhesive layer containing rotigotine after drying is preferably 10 g / m 2 to 1,000 g / m 2 , more preferably 20 g / m 2 to 800 g / m 2 .
  • the content of rotigotine or a salt thereof per unit area of the pressure-sensitive adhesive layer is preferably 0.2 to 5.0 mg / cm 2 in terms of rotigotine, more preferably 0.4 to 2. 5 mg / cm 2 , more preferably 0.6 to 2.0 mg / cm 2 , and particularly preferably 0.8 to 1.5 mg / cm 2 .
  • “rotigotine conversion” means converting the amount of rotigotine salt into the amount of free (base) rotigotine when a rotigotine salt is included.
  • the patch of the present invention contains 36 mg of rotigotine or a salt thereof in terms of rotigotine in the preparation (that is, the patch) and has an area (that is, an area in plan view of the patch) of 60 cm 2 or less.
  • an area that is, an area in plan view of the patch.
  • the area of the patch is preferably 60 cm 2 or less, more preferably 50 cm 2 or less, in the case of a preparation containing 36 mg which is the maximum maintenance dose in terms of rotigotine. 40 cm 2 or less is particularly preferable. Note that if the area (area in plan view) is too small, the handleability may be hindered. Therefore, the area (area in plan view) is preferably 1 cm 2 or more, and more preferably 2 cm 2 or more.
  • the coating liquid was applied to a silicone-treated polyethylene terephthalate (PET) film (release liner), and the rotigotine content in the pressure-sensitive adhesive layer after drying was adjusted to the amount shown in Table 1.
  • a PET film (support) was laminated on the surface of the pressure-sensitive adhesive layer, and cut into a size of 15 cm ⁇ 30 cm to obtain a target patch.
  • the SIS / SI ratio is a weight ratio.
  • the coating solution was applied to a silicone-treated PET film (release liner), prepared so that the weight of the pressure-sensitive adhesive layer after drying was 100 g / m 2 , dried in an oven at 80 ° C. for 60 minutes, but cured. No patch was obtained.
  • HPLC system high performance liquid chromatograph (LC2010C) manufactured by Shimadzu Corporation Column: ODS, 4.6 mm ⁇ ⁇ 15 cm, 5 ⁇ m Column temperature: 40 ° C
  • Table 3 shows that each of the patches of Examples 1 to 4 of the present invention has a skin permeation amount equivalent to or higher than that of a commercially available rotigotine-containing patch, and has good skin permeability. It was done. In particular, in Example 4, the rotigotine content per unit area was doubled that of a commercially available rotigotine-containing patch, and the skin permeation amount was almost doubled in the same area. This suggests the possibility of a formulation of about 1/2.
  • ⁇ Evaluation criteria for skin irritation> [Formation of erythema and crust] No erythema; 0 points Very mild (barely discernable) erythema; 1 point Clear erythema; 2 points Moderate to high erythema; 3 points Marking erythema from high erythema 4 points [formation of edema] No edema; 0 points Very mild (barely discernable) edema; 1 point Mild edema (distinguishes distinct edges due to clear bulges); 2 points Moderate edema (about 1 point bulges); 3 points Advanced edema (bulges greater than 1 mm and spread beyond the exposure range); 4 points
  • the commercially available patch containing rotigotine is P.I. I. I.
  • the value was 2.10, indicating moderate irritation.
  • the patch of the example is P.I. I. I.
  • a value of 0 was evaluated as non-irritating, indicating that skin irritation was low.
  • the commercially available rotigotine-containing patch showed significant exfoliation, but was not observed in the patch of the example. This also suggested that the skin irritation of the patch of the example was lower than that of the commercially available product.
  • the present invention provides a patch of rotigotine having sufficient skin adhesiveness but low skin irritation, good skin permeability of rotigotine, and sufficient transdermal absorption. can do.

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Abstract

La présente invention concerne un timbre adhésif qui, lorsqu'il est collé sur la peau, présente un faible pouvoir irritant cutané tout en présentant une adhérence importante sur la peau, confère des propriétés satisfaisantes de perméation transdermique à la rotigotine, et présente des propriétés suffisantes d'absorption transdermique. Le timbre adhésif inclut une couche adhésive contenant de la rotigotine ou un sel de cette dernière formée sur un support, la couche adhésive contenant de la rotigotine ou un sel de cette dernière, un élastomère thermoplastique et une huile hydrocarbonée non volatile, à un niveau dépassant 50 parts en masse, mais ne dépassant pas 800 parts en masse, pour 100 parts en masse de l'élastomère.
PCT/JP2014/062392 2013-05-08 2014-05-08 Timbre adhésif Ceased WO2014181840A1 (fr)

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JP2013-111320 2013-05-08

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016096840A1 (fr) * 2014-12-16 2016-06-23 Amarin Technologies S.A. Dispositif pour l'administration transdermique de rotigotine
CN113474043A (zh) * 2019-02-27 2021-10-01 久光制药株式会社 贴剂
US11872320B2 (en) 2021-02-25 2024-01-16 Hisamitsu Pharmaceutical Co., Inc. Method for treating osteoarthritis

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3563843A4 (fr) * 2016-12-28 2019-12-11 FUJIFILM Toyama Chemical Co., Ltd. Composition topique
JP7129501B2 (ja) * 2019-02-15 2022-09-01 久光製薬株式会社 ロチゴチン安定化方法

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WO2008044336A1 (fr) * 2006-10-11 2008-04-17 Hisamitsu Pharmaceutical Co., Inc. Préparation adhésive contenant un cristal
JP2011521974A (ja) * 2008-05-30 2011-07-28 マイラン・インコーポレーテッド 安定化された経皮薬物送達システム
JP2011219485A (ja) * 2002-07-30 2011-11-04 Ucb Pharma Gmbh ロチゴチン投与のための改善された経皮送達系
WO2012144405A1 (fr) * 2011-04-18 2012-10-26 久光製薬株式会社 Procédé de fabrication d'une pièce adhésive et pièce adhésive
WO2013035850A1 (fr) * 2011-09-08 2013-03-14 株式会社 ケイ・エム トランスダーム Préparation transdermique
JP2013079220A (ja) * 2011-10-05 2013-05-02 Yutoku Yakuhin Kogyo Kk ロチゴチン含有経皮吸収型貼付剤

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011219485A (ja) * 2002-07-30 2011-11-04 Ucb Pharma Gmbh ロチゴチン投与のための改善された経皮送達系
WO2008044336A1 (fr) * 2006-10-11 2008-04-17 Hisamitsu Pharmaceutical Co., Inc. Préparation adhésive contenant un cristal
JP2011521974A (ja) * 2008-05-30 2011-07-28 マイラン・インコーポレーテッド 安定化された経皮薬物送達システム
WO2012144405A1 (fr) * 2011-04-18 2012-10-26 久光製薬株式会社 Procédé de fabrication d'une pièce adhésive et pièce adhésive
WO2013035850A1 (fr) * 2011-09-08 2013-03-14 株式会社 ケイ・エム トランスダーム Préparation transdermique
JP2013079220A (ja) * 2011-10-05 2013-05-02 Yutoku Yakuhin Kogyo Kk ロチゴチン含有経皮吸収型貼付剤

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016096840A1 (fr) * 2014-12-16 2016-06-23 Amarin Technologies S.A. Dispositif pour l'administration transdermique de rotigotine
CN113474043A (zh) * 2019-02-27 2021-10-01 久光制药株式会社 贴剂
CN113474043B (zh) * 2019-02-27 2024-05-14 久光制药株式会社 贴剂
US11872320B2 (en) 2021-02-25 2024-01-16 Hisamitsu Pharmaceutical Co., Inc. Method for treating osteoarthritis

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